1. Field of the Invention
The present invention concerns devices, methods, compositions and formulations for vaginal delivery of a class of drugs in the bisphosphonate group. In particular, the invention concerns a targeted site delivery of bisphosphonates to the vagina using a bisphosphonate comprising vaginal composition or a medicated intravaginal device comprising the bisphosphonate composition formulated for transvaginal delivery. The composition or the device of the invention delivers 10 to 30 times more bisphosphonates intravaginally as can be delivered orally due to the absorption of bisphosphonates from the vagina which far exceeds the absorption of bisphosphonates from the gastrointestinal tract. Vaginal administration generally avoids major problems connected with oral administration, such as gastric and esophageal reflux and ulceration.
The invention also concerns a method for treatment of osteoporosis, Paget""s disease, metastatic cancer of bone, and other related diseases of bone and skeleton and for prevention of bone breakdown and loss of bone mass and strength by intravaginal administration of bisphosphonates via the vagina and by transvaginal delivery of bisphosphonates to general circulation. This novel and unique route of administration provides a mechanism for delivering drugs to prevent and treat osteoporosis in a way now only available with considerable side effects.
2. Background and Related Art
Osteoporosis and therewith associated loss of bone mass and strength leading to bone breakdown and fractures is a major medical problem in postmenopausal women.
It is estimated that eight million women in the United States have osteoporosis and that an additional 15.4 million women have low bone mass, placing them at increased risk for development of osteoporosis. These risks are most profound after menopause when the rate of bone loss is accelerated. Osteoporosis leads to fractures in the spine and hips in a significant number of these women, markedly altering their lifestyle and reducing their life expectancy.
In the past decade, hormone replacement therapy with estrogens has been the mainstay in the treatment of post-menopausal women. Recent studies, however, have shown that this treatment is not suitable for all female patients and that it possesses an increasing risk of certain female cancers and the heightened malignancy of cancers once they occur. For that reason, alternate therapies for osteoporosis have been and are continually sought.
A number of approaches for prevention of osteoporosis in this patient group have been proposed. These approaches include the administration of high doses of calcium and vitamin D in conjunction with the administration of estrogens, and the administration of synthetic substances which bind to estrogen receptors such as raloxifen, tamoxifen, etc.
One of the new approaches which has been suggested and investigated is the administration of bisphosphonates. Bisphosphonates prevent the resorption of bone, thereby reducing occurrences of fractures, especially of the spine and hip. Recent studies have demonstrated these compounds act to prevent the loss of bone and to enhance bone density in the postmenopausal female population and in patients with Paget""s disease of bone (Journal of Clinical Endocrinology and Metabolism, 82(1):265-274 (1997); Journal of Bone and Mineral Research. 12(10):1700-1707 (1997); American Journal of Medicine, 106(5):513-520 (1997); Journal of Clinical Endocrinology and Metabolism. 83(2):396-402 (1998)).
As described in the above references, bisphosphonates have recently been shown to prevent the continuous breakdown of bone in the vulnerable population and lead to strengthening of bone and an increase in bone mass. In several studies, these compounds have been shown to markedly reduce fractures.
In addition to treating osteoporosis and Paget""s disease, the clinical use of bisphosphonates for cancer has increased dramatically in recent years. New England Journal of Medicine, 335:1785-1791 (1996) reports that treatment with bisphosphonates decreases the frequency of skeletal events for patients with multiple myeloma involving bone and breast cancer with osteolytic metastases. Recent clinical trials have shown that adjunctive treatment with bisphosphonates reduces the incidence and number of new bone and visceral metastases in women with high risk, primary breast cancer (New England Journal of Medicine. 339:398-400 (1998)).
There are at least ten bisphosphonates now available for therapy worldwide, but major problems with their administration have been noted.
The main problems with oral administration of bisphosphonates relate to absorption and gastrointestinal tolerability. Absorption is poor and drug administration recommendations must be given to the patient and checked. Etidronate, tiludronate and risedronate need to be taken two hours before or after a meal with a large volume of water, and dairy products or antacids are forbidden within two hours of administration. Alendronate has been given in the early morning, immediately upon rising, while in the upright position, two hours before any food or drink. Upper gastrointestinal adverse effects are reported in 15-20% of patients with orally administered bisphosphonates. Esophagitis has been reported in a small number of patients with osteoporosis treated with 10 mg/day alendronate. (Drugs, 58:827 (1999)).
Generally, thus, the bisphosphonates oral administration requires a strict regimen. In most patients, this regimen has proven to be inconvenient and impractical leading to a failure of oral administration.
In addition, a significant number of women taking these compounds develop irritation of esophageal mucosa, esophageal reflux and esophagitis (Digestive Diseases and Sciences, 43(9):1998-2002 (1998); Digestive Diseases and Sciences, 43(5):1009-1015 (1998)).
Even if these inconveniences and complications could be overcome, to deliver a sufficient amount of bisphosphonates is also problematic because only less than 1% of the bisphosphonates are generally absorbed following oral administration (Drugs, 53(3):415-434 (1997). For these reasons, as many as 35% all patients discontinue the oral treatment with bisphosphonates in one year.
Thus, it would be very important to provide an alternative composition and/or drug delivery route which would avoid problems associated with bisphosphonate oral administration and still provide a patient with a therapeutically effective amount of bisphosphonates.
The major difficulties encountered with the administration of bisphosphonate compounds are their poor absorption from the gastrointestinal tract, their interaction with other drugs and foods which alters their absorption, and their tendency to damage mucosa and irritate the esophagus and stomach.
In view of the problems encountered with oral administration of bisphosphonates which limits their utility, it is clear that new delivery mechanisms which would enhance the absorption and bioavailability of these drugs, especially transvaginal administration with sustained-release administration would be extremely advantageous for achieving and increasing a therapeutic potential of bisphosphonates.
It is, therefore, an objective of the present invention to provide devices, methods and compositions for treating osteoporosis, Paget""s disease and other related diseases of bone and skeleton or for treating and prevention of cancer by intravaginal delivery of effective doses of bisphosphonates to the vagina and by transvaginal transport of bisphosphonates into the general circulation after absorption of these drugs through a vaginal mucosa.
All references, patents and patent applications cited herein are hereby incorporated by reference in their entirety.
One aspect of the present invention is a device, a method, a composition, and a formulation for transvaginal delivery of bisphosphonates effective to treat osteoporosis, Paget""s disease and other related diseases of bone and skeleton, into the general circulation.
Another aspect of this invention is a pharmaceutically acceptable composition for intravaginal delivery comprising a bisphosphonate selected from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate formulated for effective transvaginal absorption for prevention and treatment of osteoporosis, Paget""s disease, other diseases of bone and skeleton and cancer.
Still yet another aspect of this invention is a pharmaceutically acceptable composition comprising a bisphosphonate, selected from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate, in dosage unit form, for intravaginal delivery to a human female for the purpose of treating or prevention of osteoporosis, Paget""s disease, other diseases of bone and skeleton or cancer wherein said composition comprises a combination of an effective amount of the bisphosphonate with a nontoxic pharmaceutically acceptable excipient carrier, a mucoadhesive and/or penetration enhancing agent, wherein said composition is a vaginal suppository, tablet, bioadhesive tablet, capsule, microparticle, bioadhesive microparticle, cream, lotion, foam, ointment, solution, gel, or a sustained release gel, tablet or capsule, or a sustained release suppository administered directly to the vagina or incorporated into a device of the invention.
Still another aspect of this invention is a medicated intravaginal device, such as a medicated tampon, tampon-like device, pessary, ring, sponge, or cup comprising a bisphosphonate selected from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate in a formulation suitable for intravaginal absorption and transvaginal delivery of the bisphosphonate agent to the general circulation.
Yet another aspect of this invention is a device for delivering intravaginally an effective amount of a bisphosphonate agent selected from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate for treatment of osteoporosis, Paget""s disease, metastatic cancer of bone, other bone or skeleton diseases or cancer and prevention of development of osteoporosis, wherein said device is a ring, strip, vaginal tampon, absorbent vaginal tampon, strip, capsule or suppository comprising tampon or tampon-like device.
Still yet another aspect of this invention is a method for treating a female patient suffering from, or being at risk of developing osteoporosis, Paget""s disease, metastatic cancer to bone or other disease of bone or skeleton or cancer, said method comprising contacting the vaginal epithelium of the female patient with a composition comprising a therapeutically effective dose of bisphosphonate selected from the group consisting of alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate in admixture with a biocompatible pharmaceutically acceptable excipient for administration of the bisphosphonate to the vaginal epithelium, wherein said bisphosphonate is present in a pharmaceutical composition in an amount sufficient to attain, following intravaginal delivery of the composition and its absorption through the vaginal mucosa and transportation via venous and lymphatic channels to the circulation, a therapeutically effective amount of the bisphosphonate in the blood circulation of the patient.
Another aspect of this invention is a method for preparation of an intravaginal medicated device comprising incorporating a composition comprising a bisphosphonate agent selected from the group alendronate, clodronate, etidronate, pamidronate, tiludronate, ibandronate, zoledronate, olpadronate, residronate and neridronate with a device for intravaginal delivery of said agent, wherein said device is a vaginal tampon, a strip, capsule or container comprising tampon or a tampon-like device, vaginal strip, vaginal cup, vaginal ring, vaginal pessary, vaginal tablet, vaginal suppository, vaginal sponge, bioadhesive tablet, microparticle, or bioadhesive microparticle, and wherein said agent is formulated as a cream, lotion, foam, ointment, solution or gel.